Hexyl 5-aminolevulinate

INDICATIONS AND USAGE Cysview is indicated for use in the cystoscopic detection of carcinoma of the bladder, including carcinoma in situ (CIS), among patients suspected or known to have lesion(s) on the basis of a prior cystoscopy, or in patients undergoing surveillance cystoscopy for carcinoma of the bladder. Cysview is used with the Karl Storz D-Light C Photodynamic Diagnostic (PDD) system to perform Blue Light Cystoscopy (BLC ® ) as an adjunct to the white light cystoscopy. Cysview is an optical imaging agent indicated for use in the cystoscopic detection of carcinoma of the bladder, including carcinoma in situ (CIS), among patients suspected or known to have lesion(s) on the basis of a prior cystoscopy, or in patients undergoing surveillance cystoscopy for carcinoma of the bladder. Cysview is used with the Karl Storz D-Light C Photodynamic Diagnostic (PDD) system to perform Blue Light Cystoscopy (BLC ® ) as an adjunct to the white light cystoscopy. Important Limitations of Use: Not a replacement for random bladder biopsies or other procedures used in the detection of bladder cancer. ( 1.1 , 5.2 ) 1.1 Limitations of Use Cysview is not a replacement for random bladder biopsies or other procedures used in the detection of bladder cancer [ see Warnings and Precautions (5.2) ].

DOSAGE AND ADMINISTRATION Training in blue light cystoscopy with the Karl Storz D-Light C PDD system is essential prior to the use of Cysview. ( 2.5 ) Reconstitute Cysview powder with the supplied 50 mL DILUENT under aseptic conditions. ( 2.2 ) Use solution of Cysview shortly after reconstitution. If unable to use, the solution may be stored for up to 2 hours in a refrigerator at 2°-8°C (36°-46°F) in the labeled syringe. Discard after 2 hours. ( 2.2 , 16 ) Instill 50 mL of reconstituted solution of Cysview into the emptied bladder via an intravesical catheter. Retain in the bladder for 1 hour before evacuating and performing cystoscopic examination. ( 2.3 , 2.5 ) First perform a complete cystoscopic examination of the entire bladder under white light and then repeat the examination of the entire bladder under blue light. Record and document information about location and appearance of suspicious lesions and areas seen under both white and blue light. ( 2.5 ) 2.1 Recommended Dose The recommended dose for adults is 50 mL of reconstituted solution of Cysview [ see Dosage and Administration (2.2) ], instilled into the bladder via a urinary catheter [ see Dosage and Administration (2.3) ]. 2.2 Reconstitution of Cysview Cysview is supplied as a kit containing: a clear glass vial labeled as Cysview (hexaminolevulinate HCl) for Intravesical Solution containing 100 mg hexaminolevulinate hydrochloride as a powder, a prefilled syringe labeled as DILUENT for Cysview containing 50 mL of the diluent, and a catheter adapter. The kit may be supplied as two options; with or without a vial adapter for use during reconstitution. Perform all steps under aseptic conditions. Wear gloves during the reconstitution procedure; skin exposure to hexaminolevulinate hydrochloride may increase the risk for sensitization to the drug. Cysview Powder Cysview Diluent Plunger Rod Figure 1. Figure 1 Figure 1a Reconstitution Using a Vial Adapter Fasten the plunger rod into the rubber stopper of the prefilled syringe by turning the plunger rod clockwise until it stops (Figure 1). Figure 2. Remove the plastic cap from the vial. Remove the TyveK® cover from the vial adapter blister package. Do not remove the vial adapter from the package. Place the Cysview vial on a flat surface. Using the blister package to hold the vial adapter, connect to the vial with a downward vertical motion. The vial adapter snaps onto the vial as the spike penetrates the rubber stopper of the vial. Remove the plastic blister package and discard it. Take care not to touch the exposed end of the vial adapter (Figure 2). Figure 3. Remove the cap from the prefilled syringe and carefully retain it for subsequent reattachment to the syringe. Hold the prefilled syringe upright and carefully press the plunger rod upward to remove air. Connect the syringe to the vial adapter. Inject about 10 mL of the diluent from the prefilled syringe down into the vial. The vial should be about ¾ full (Figure 3). Figure 4. Without disconnecting the vial adapter from the vial, hold the vial and syringe in a firm grip (Figure 4) and gently shake to dissolve the powder in the diluent. The powder normally dissolves almost immediately. Figure 5. Turn the vial upside down and withdraw all of the dissolved solution from the vial back into the syringe (Figure 5). Do not inject large amounts of air or diluent when vial is inverted as it may block the venting action of the vial adapter. If this occurs, turn the vial upright and pull back on the plunger rod in the syringe. Figure 6. Disconnect the empty vial with the vial adapter from the syringe tip and discard it. Plug the syringe with the syringe cap (Figure 6). Gently mix the contents of the syringe. The reconstituted solution of Cysview is colorless to pale yellow and clear to slightly opalescent, and free from visible particles. Peel off the detachable portion of the syringe label. On the syringe label, add two hours to the present time and write the resulting expiration time and date. Cysview is now reconstituted and ready for use. The solution of Cysview contains 2 mg/mL of hexaminolevulinate hydrochloride. Instill the reconstituted solution of Cysview into the bladder [ see Bladder instillation of Cysview (2.3) ]. If unable to administer the solution shortly after reconstitution, store the solution for up to 2 hours in a refrigerator at 2°-8°C (36°- 46°F) in the labeled syringe. If not used within 2 hours, discard the solution [ see How Supplied/Storage and Handling (16) ]. Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Reconstitution Without the Use of a Vial Adapter Fasten the plunger rod into the rubber stopper of the prefilled syringe by turning the plunger rod clockwise until it stops (Figure 1). Figure 7. Remove the plastic cap from the vial. Remove the cap from the prefilled syringe and carefully retain it for subsequent reattachment to the syringe. Attach a needle to the prefilled syringe. Hold the prefilled syringe upright and carefully press the plunger rod upward to remove air. Penetrate the stopper of the Cysview vial with the needle and inject about 10 mL of the diluent from the prefilled syringe down into the vial. The vial should be about ¾ full (Figure 7). Figure 8. Without withdrawing the needle from the vial, hold the vial and syringe in a firm grip (Figure 8) and gently shake to dissolve of the powder in the diluent. The powder normally dissolves almost immediately. Figure 9. Turn the vial upside down and withdraw all of the dissolved solution from the vial back into the syringe (Figure 9). Figure 10. Remove the needle from the vial, disconnect the needle from the syringe tip and discard it. Plug the syringe with the syringe cap (Figure 10). Gently mix the contents of the syringe. The reconstituted solution of Cysview is colorless to pale yellow and clear to slightly opalescent, and free from visible particles. Peel off the detachable portion of the syringe label. On the syringe label, add two hours to the present time and write the resulting expiration time and date. Cysview is now reconstituted and ready for use. The solution of Cysview contains 2 mg/mL of hexaminolevulinate hydrochloride. Instill the reconstituted solution of Cysview into the bladder [ see Bladder instillation of Cysview (2.3) ]. If unable to administer the solution shortly after reconstitution, store the solution for up to 2 hours in a refrigerator at 2°-8°C (36°- 46°F) in the labeled syringe. If not used within 2 hours, discard the solution [ see How Supplied/Storage and Handling (16) ]. Figure 7 Figure 8 Figure 9 Figure 10 2.3 Bladder Instillation of Cysview For bladder instillation of the solution of Cysview, use straight or intermittent, urethral catheters with a proximal funnel opening that will accommodate the Luer Lock adapter. Use only catheters made of vinyl (uncoated or coated with hydrogel), latex (amber or red), and silicone to instill the reconstituted Cysview. Do not use catheters coated or embedded with silver or antibiotics. In-dwelling bladder catheters (Foley catheters) may be used if the catheters are inserted shortly prior to Cysview administration and are removed following the Cysview instillation. Use the following steps for bladder instillation of Cysview: Using standard sterile catheterization technique, first insert the urethral catheter into the bladder of the patient and use the catheter to completely empty the patient's bladder before instillation of Cysview. Figure 11. To attach the syringe containing the solution of Cysview to the catheter, do the following: Remove the syringe cap from the syringe that contains the reconstituted solution of Cysview. Attach the Luer Lock end of the (provided) catheter adapter to the syringe. Insert the tapered end of the catheter adapter into the funnel opening of the catheter. See Figure 11 , with the connection enlarged in the inset. Slowly instill the solution of Cysview into the bladder through the catheter (Figure 11), ensuring that t

WARNINGS AND PRECAUTIONS Anaphylaxis: have trained personnel and therapies available. ( 5.1 ). Failed Detection: Cysview may not detect all malignant lesions. Always perform white light cystoscopy followed by blue light cystoscopy. Do not biopsy with blue light only. ( 5.2 ) False fluorescence may occur due to inflammation, cystoscopic trauma, scar tissue, previous bladder biopsy, recent BCG therapy or chemotherapy. ( 5.3 ) 5.1 Anaphylaxis Anaphylaxis, including anaphylactoid shock, has been reported following administration of Cysview [ see Adverse Reactions (6.2) ]. Prior to and during use of the Cysview, have trained personnel and therapies available for the treatment of anaphylaxis. 5.2 Failed Detection Cysview may fail to detect some bladder tumors, including malignant lesions. Cysview is not a replacement for random biopsies or any other procedure usually performed in the cystoscopic evaluation for cancer. Do not perform cystoscopy with blue light alone as malignant lesions can be missed unless the bladder is initially examined under white light [ see Dosage and Administration (2.5) and Clinical Studies (14) ]. 5.3 False Positive Fluorescence Fluorescent areas detected during blue light cystoscopy may not indicate a bladder mucosal lesion. In the controlled clinical studies, approximately 20% of the lesions detected only by blue light cystoscopy showed neither dysplasia nor carcinoma [ see Clinical Studies (14) ]. False positive fluorescence may result from inflammation, cystoscopic trauma, scar tissue or bladder mucosal biopsy from a previous cystoscopic examination, and recent BCG immunotherapy or intravesical chemotherapy. In a study of patients treated with recent BCG immunotherapy or intravesical chemotherapy, the rate of false positives with blue light was 55% between 6 weeks to 90 days and 41% after 90 days; the false positive rate was 53% and 33% at the respective time intervals with white light. The presence of urine and/or blood within the bladder may interfere with the detection of tissue fluorescence. To enhance the diagnostic utility of Cysview with the Karl Storz D-Light C PDD System: ensure the bladder is emptied of urine prior to the instillation of fluids at cystoscopy; biopsy/resect bladder mucosal lesions only following completion of both white light and blue light rigid cystoscopy;

CONTRAINDICATIONS Cysview is contraindicated in patients with: porphyria, gross hematuria, known hypersensitivity to hexaminolevulinate or any derivative of aminolevulinic acid. Do not use Cysview in patients with: porphyria, gross hematuria, known hypersensitivity to hexaminolevulinate or aminolevulinate derivatives. ( 4 )

DRUG INTERACTIONS No specific drug interaction studies have been performed.

ADVERSE REACTIONS Anaphylaxis has been reported following exposure to Cysview [ see Warnings and Precautions (5.1) ]. The most common adverse reaction reported in patients who received Cysview was bladder spasm, occurring in 2% of patients, followed by dysuria, hematuria and bladder pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Photocure Inc. at 1-855-297-8439 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Study Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In seven clinical trials, safety data were obtained from 1,628 patients, aged 32 to 96 years with a median age of 70 years, all primarily Caucasian and approximately 75% male. All patients were evaluated after a single instillation of 50 mL solution of Cysview, and 103 patients received a repeat administration of Cysview. Of these patients, 170 (10.4%) patients reported at least one adverse reaction. The most common adverse reaction was bladder spasm (reported in 2.0% of the patients) followed by dysuria, hematuria, and bladder pain. No patients experienced anaphylaxis. In the randomized controlled clinical study, adverse reactions were similar in nature and rate between the study drug group and the control group. In a controlled study using Cysview in the surveillance setting, adverse reaction types were similar [ see Clinical Studies (14) ]. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of Cysview. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Anaphylactoid shock, hypersensitivity reactions, bladder pain, cystitis and abnormal urinalysis have been reported during post-marketing use of Cysview.

Mechanism of Action Cysview is an ester of the heme precursor, aminolevulinic acid. After bladder instillation, Cysview enters the bladder mucosa and is proposed to enter the intracellular space of mucosal cells where it is used as a precursor in the formation of the photoactive intermediate protoporphyrin IX (PpIX) and other photoactive porphyrins (PAPs). PpIX and PAPs are reported to accumulate preferentially in neoplastic cells as compared to normal urothelium, partly due to altered enzymatic activity in the neoplastic cells. After excitation with light at wavelengths between 360 and 450 nm, PpIX and other PAPs return to a lower energy level by fluorescing, which can be detected and used for cystoscopic detection of lesions. The fluorescence from tumor tissue appears bright red and demarcated, whereas the background normal tissue appears dark blue. Similar processes may occur in inflamed cells.